Demand for viable organs far exceeds the current supply. In 2011, it is predicted that over 70% of the people placed on the waiting list for organ transplantation will not receive a donor organ (see world wide web at: “opt.transplant.hrsa.gov” as of Apr. 22, 2011), and this disparity between the number of organs available and the number of organs required continues to grow: the increasing rate at which organ transplantation is prescribed outpaces the slow increase in the number of donors each year. It has been suggested that the actual need is much larger, and if the demand could be entirely met, over 30% of all deaths in the United States could be substantially postponed. Additionally, there is a constant demand for enormous numbers of high quality cells such as hepatocytes in the fields of cell transplantation, pharmacotoxicology, tissue engineering, and bioartificial assist devices. The scarcity of viable organs, for example liver and resultant necessitates the use of suboptimal sources including damaged donor organs that are not transplantable. Many of these organs have potentially reversible pathologies however, that could be treated via ex vivo perfusion thereby increasing their cell yield.
One of the greatest problems in donor organ transplantation is the storage and preservation of organs from the time of harvest from a donor to the time of transplantation into a recipient. The amount of time that can lapse between the two events is quite limited because the cells and tissues of the donor organ deteriorate over time, even if they are stored at refrigerated temperatures. Once harvested, cells and tissues are deprived of the oxygen that is required to maintain internal metabolism and cell volume integrity. To counteract the ill effects of low oxygen, standard techniques for modern organ preservation involve the exposure of a harvested organ to preservation solutions at cold temperatures not below 0° C. Although colder temperatures are a solution to oxygen deprivation in donor organ tissue, they present their own problems. Cold or hypothermic conditions may lead to cellular damage including a reduced ability to generate energy, maintain cell volume integrity, and also swelling and/or cell death.
Organs can only be kept viable for transplant for a limited time between the donation and the transplant operation. As soon as an organ is recovered from a donor, the clock starts ticking to meet the deadline to get it transplanted into a waiting recipient. Currently, the organs that can be transplanted and how long the organ can be out of the body before transplantation are as follow: heart and lungs 4-6 hours; pancreas, liver, and intestine 12-24 hours, kidneys 48-72 hours. Further hepatocytes are usually only viable for transplanting within 12 hours.
There are currently approximately 100,000 patients on the organ transplant waiting list in the US; a number that far exceeds the supply of available organs and the waiting list continues to grow at about 5% each year. The most promising strategies that are being explored as a means for addressing this critical shortage are: 1) bioartificial tissue and organ construction, which aims to manufacture tissue and organ analogues in vitro, and 2) donor organ revitalization methodologies, the goal of which is to recondition marginally damaged organs for transplantation. For both these approaches to be clinically successful, considerable effort must be expended on developing effective biopreservation methodologies. The current gold standard for whole organ preservation is cold storage on ice during which time the organ continuously deteriorates, and does not remain viable for any length of time, e.g., heart and lungs remain only viable for only 4-6 hours; pancreas, liver, and intestine remain only viable for only 12-24 hours, and kidneys remain only viable for only 48-72 hours Currently, the vast majority of efforts to develop improved cryopreservation and desiccation techniques focus on the preservation of individual cell populations, as the necessary strict control of temperature and concentration gradients are impossible to achieve in macroscopic tissues and organs, whether they be artificial or natural.
Simple cold storage remains the only option for tissue preservation. While cryopreservation has the potential, in theory, for very long storage of organs, successful and viable preservation of tissues and organs has proven elusive and very difficult (Fahy, G. G., Wowk, B. and Wu, J. Cryopreservation of complex systems: the missing link in the regenerative medicine supply chain. Rejuvenation Research 9, 279-291 (2006). A superior biopreservation method that extends the tissue storage time beyond current limits has yet to be developed. Such a method would be truly transformative for tissue and organ preservation, tissue and organ transport, and tissue and organ transplantation.
Storage of organs at sub-zero temperatures is extremely difficult because the tissue and water in the organ usually freezes. These relatively lower temperature ranges cause damage or destruction to the cells and tissues. There are some preservations solutions currently available for organ storage purposes, e.g., Viaspan™, which is used for cold (above 0° C.) storage, although their capacity to store organs effectively is significantly limited to the fact that they can only extend the storage of organs to a maximum of 36 hours before organs begin to deteriorate. For example, the preservation of donor organs using Viaspan™ preservation solution (also commonly known as University of Wisconsin (UW) solution, manufactured by DuPont) only extends the storage of kidney organs to a maximum of 36 hour period before the organs begin to deteriorate. For example, if kidneys are perfused with UW solution and packed on ice, surgeons will attempt to use them within 24 hours but not later than 36 hours after harvesting. A principal problem however is that the viability of the donor kidney decreases over time of storage so that by 36 hours there is at least some damage to the tubular cells. This generally results in decreased viability of the kidney cells so that urine production and proper kidney function are delayed after transplant. As a result, artificial kidney function or dialysis is generally required for full recovery of a recipient after transplantation.
Perfusion systems are capable of significantly impacting the viability of transplantable organs by optimally supporting donor organs during storage, and recovering reversibly damaged tissues through perfusate-based treatment protocols (Tolboom, et al., Transplantation, 2009, 87 (2): p. 170-7; St Peter, et al., British Journal of Surgery, 2002, 89: p. 609-616.).
In summary, there is an urgent need for improved preservations technologies, especially for tissues and organs. Accordingly, there is a need for improved solutions and methods for effective organ preservation for extended periods of time. To facilitate the translation of this technology to clinical use, comprehensive and dynamic analyses of organ function during perfusion are needed that identify parameters critical to organ stability and recovery.
It is estimated that every year 27,000 people die because of liver-failure; currently the twelfth leading cause of death in the US. The only known treatment is orthotopic liver transplantation. According to the Organ Procurement and Transplantation Network, over 10,000 patients are added to the waiting list and less than 7,000 receive transplants each year. Clinically, the decision to use a non-ideal donor liver for transplantation is a difficult choice that to date lacks an accurate measure, and is done primarily based on gross organ morphology and donor statistics such as age and cause of death. A large number of organs, for instance kidneys, are not transplanted due to fear of graft failure based on qualitative tests that are open to interpretation. It is estimated that with the current practice about 3,000 viable cadaveric livers go unused. It is further estimated that about 6,000 ischemic livers could be reconditioned for transplantation, dramatically increasing the availability of grafts; currently these organs are discarded due to lower survival rates for these marginal grafts.
Accordingly, an accurate and reliable system for the analysis, prediction, and optimization of to predict organ viability, and to determine best method of organ preservation is greatly needed, and would provide significant benefit to increase the number of organs in a viable condition for transplant, and reduce the number of deaths caused by inaccessibility to organ transplantation, e.g., such methods may reduce liver failure caused deaths in the order of hundreds to thousands of patients per year. The broader impacts of such a method for prediction of liver viability would be very tangible both clinically and scientifically.